| Abstrakt: |
Introduction: Visceral leishmaniasis (VL) is caused by Leishmania donovani. The purine and pyrimidine pathways are essential for L. donovani. Simultaneously inhibiting multiple targets could be an effective strategy to eliminate the pathogen and treat VL. Objective: We aimed to target the essential enzymes of L. donovani and inhibit them using a multi‐target approach. Materials and methods: A systematic analytical method was followed, in which first reported inhibitors of two essential enzymes (adenine phosphoribosyl‐transferase [APRT] and dihydroorotate dehydrogenase [DHODH]) were collected and then ADMET and PASS analyses were conducted using the Lipinski rule and Veber's rule. Additionally, molecular docking between screened ligands and proteins were performed. The stability of complexes was analyzed using molecular dynamics (MD) simulations and MMPBSA analysis. Results: Initially, 6,220 unique molecules were collected from the PubChem database, and then the Lipinski rule and Veber's rule were used for screening. In total, 203 compounds passed the ADMET test; their antileishmanial properties were tested by PASS analysis. As a result, 15 ligands were identified. Molecular docking simulations between APRT or DHODH and these 15 ligands were performed. Four molecules were found to be plant‐derived compounds. Lig_2 and Lig_3 had good docking scores with both proteins. MD simulations were performed to determine the dynamic behavior and binding patterns of complexes. Both MD simulations and MMPBSA analysis showed Lig_3 is a promising antileishmanial inhibitor of both targets. Conclusion: Promising plant‐derived compounds that might be used to combat VL were obtained through a multi‐target approach. The public health hazard posed by visceral leishmaniasis is significant, and there are currently no effective medications. A multi‐target approach utilizing various screening strategies was used to obtain promising ligands. Together, the screening of molecules, molecular docking, MD simulations, and MMPBSA investigation suggest that Lig_3 (PubChem CID‐44610153) can be considered a lead inhibitor compound of APRT and DHODH of L. donovani. The findings of this study may serve as a reference in the field of medicine and other related research. [ABSTRACT FROM AUTHOR] |
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